Inflammatory bowel disease is believed to result from an inappropriate immune response to commensal intestinal microbes in a genetically susceptible host. Aberrant sensing of microbes by the innate immune system triggers the development of pathogenic T lymphocytes that initiate and propagate intestinal inflammation. We have previously shown that a T lymphocyte responding against a microbial pathogen appears to undergo asymmetric division to give rise to two differentially fated daughter cells (Chang et al., Science 2007). We have also recently provided evidence for a novel mechanism of asymmetric division whereby asymmetric localization of the proteasome, and consequently unequal degradation of factors targeted for destruction during mitosis, yields unequal partitioning of a key fate determinant to daughter cells (Chang et al., Immunity, in press). Preliminary evidence from our laboratory using an adoptive transfer model of colitis suggests that CD4+ T cells may undergo asymmetric division during a dysregulated immune response to commensal intestinal microbes. In this proposal, we will: (1) determine whether asymmetric segregation of the proteasome is evident in dividing CD4+ T cells undergoing a dysregulated immune response to commensal microbes; and (2) determine whether inhibition of proteasome activity disrupts the ability of CD4+ T cells to cause intestinal inflammation. Accomplishment of the aims of this proposal may yield important insights into a novel mechanism that may regulate the pathogenesis of inflammatory bowel disease, and may identify a new pathway against which therapies could be directed.